An association between infection and suboptimal regenerative outcomes has often been described in the periodontal and oral surgical literature. It is also increasingly recognized that low-level bacterial contamination can play a role in "aseptic" loosening of total joint implants. In this context, the term "infection" does not refer to fulminating, acute processes, but to subclinical, indolent infections characterized by colonization of substrates. In these conditions, microbial contaminants initiate synthesis of potent pro-inflammatory cytokines by local cells. These primary mediators, in turn, stimulate production of secondary mediators that amplify the inflammatory response. The end result is secretion of tissue-degrading enzymes and eventually osteoclastic bone resoprtion. In this project, a multidisciplinary team approach will be used to develop proactive, multifunctional devices for localized bone regeneration in sites compromised by oral microbes by attacking the problems of microbial contamination, inflammation, tissue destruction, and hindered tissue repair. In Aim 1, a controlled release system for sequential delivery of multiple biomolecules will be developed. With respect to this Aim, it is hypothesized that the devices can be tailored to deliver antibacterial, anti-inflammatory, anticatabolic, and anabolic compounds with discrete profiles that ensure appropriate bioactivity. In Aim 2, devices selected from Aim 1 will be investigated for their ability to control microbial bioburden and inflammation as well as to inhibit bone resorption and to promote bone formation in vitro, and material degradation and drug release will be correlated with in vivo findings. It is hypothesized that biomolecules released from the devices will kill oral microbes, decrease osteoclastic differentiation/activity, and increase osteoblastic differentiation/activity. In Aim 3, complete devices providing individual, sequential, combined, and simultaneous drug release profiles will be tested for their biological activity in vivo using a canine peri- implantitis model. It is hypothesized that sequential treatment of the different phases of the disease process with a unitary device will be more effective than the common approach of treating only one of the components. The findings of these studies will contribute to understanding of the chain of biological events that occurs during bacterially-induced inflammatory bone destruction, and they will progress the field of biomedical device development toward more effective means for enhancing bone regeneration in an oral microbial environment. PUBLIC HEALTH RELEVANCE: Colonization of natural and synthetic biomaterials by bacteria elicits a cascade of local tissue reactions that ultimately lead to loss of the supportive structures. Such tissue destruction is at the heart of many conditions, including infected teeth, bones, dental implants, and joint implants. This project will develop multifunctional, unitary, controlled release devices that halt the detrimental processes and stimulate localized tissue repair in sites compromised by bacteria.